Alkylation via Enolate Anions

Acetylenedimagnesium bromide, 66, 84, 137 Acyl-alkyl diradical disproportionations, 299 Acyl-alkyl diradical recombination, 296 Alkaline hydrogen peroxide, 10, 12, 20 Alkylation of formyl ketones, 93 Alkylation via enolate anions, 86 17a-Alkynyl steroids from 17-ketones, 67 2a-Al]yl-17jS-hydroxy-5a-androstan-3 -one, 9 5 Allylic acetoxylation, 242 Allylmagnesium bromide, 64 17 -Aminoandrost-5-en-3 -ol, 145 17 a-Aminomethy 1-5 a-androstane-3, 1718-diol, 387... 

Isatin is a stable, bright orange solid that is commercially available in large quantities. Because it readily undergoes clean aromatic substitution reactions at C-5, iV-alkylation via an anion, and ketonic reactions at the C-3-carbonyl group, for example enolate addition, it is a very useful intermediate for the synthesis of indoles and other heterocycles. 

LithiumJliq. ammonia Reductive a-alkylation of ketones via enolate anions... 

OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

The normal U-shaped Hammett plots were found for both the catalysed [by a copper(II)salen complex (31)] and uncatalysed asymmetric alkylation of enolates by substituted benzyl bromides,126 indicating that both reactions occur via an. S N2 mechanism (Scheme 15). Because both reactions were faster when electron-withdrawing substituents were on the benzyl bromide, it was concluded that there was more bond formation than bond rupture in the. S N2 transition states. Because the curvature of the Hammett plot was greater for the catalysed reaction, it was concluded that the catalysed reaction has a later transition state with a greater negative charge on Ca. The role of the catalyst was to increase the nucleophilic character of the enolate anion. 

Although alkylation with these anions is usually a high-yielding reaction, there are several possible side-reactions that must be eliminated by careful choice of reaction conditions494 98. These side-reactions include O-alkylation and multiple C-alkylations. The yields of alkylation reactions with anions is often significantly reduced if the halide is unable to react via a S -type process. This may be alleviated to some extent by the use of trimethylsilyl enol ethers using Lewis acid catalysis499 503. 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

One can speed up alkylation relative to elimination by stabilizing an enolate anion with an additional ewg, making the anion softer and less basic. For example, the acidic CH2 of malonates, CH2(COOEt>2, or acetoacetates, CH3COCH2COOEt, deprotonates easily and makes an excellent nucleophile. The ester can later be hydrolyzed to the acid (Section 8.8.1) and removed by decarboxylation via path Ei. This ester is a detachable ewg that makes the enolate less basic and softer, favoring substitution over elimination. 

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